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17 results on '"Immunité et cancer ( U932 )"'

1. Inhibition of effector antigen-specific T cells by intradermal administration of heme oxygenase-1 inducers

Author

Julien Pogu, Philippe Blancou, Maud Maquigneau, Frédéric Brau, Séverine Remy, Thomas Simon, Ignacio Anegon, Sylvie Pogu, Jean-François Fonteneau, Gilles Blancho, Eliane Piaggio, Nicolas Poirier, Bernard Vanhove, Centre de Recherche en Transplantation et Immunologie ( U1064 Inserm - CRTI - CHU Nantes ), Hôtel-Dieu de Nantes-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université de Nantes ( UN ) -Centre hospitalier universitaire de Nantes ( CHU Nantes ), Center for Vascular and Inflammatory Diseases [Baltimore, USA], University of Maryland School of Medicine [Baltimore], Immuno-Endocrinologie Cellulaire et Moléculaire [Nantes] ( IECM ), Université de Nantes ( UN ) -Ecole Nationale Vétérinaire, Agroalimentaire et de l'alimentation Nantes-Atlantique ( ONIRIS ) -Institut National de la Recherche Agronomique ( INRA ), Institut de pharmacologie moléculaire et cellulaire ( IPMC ), Université Nice Sophia Antipolis ( UNS ), Université Côte d'Azur ( UCA ) -Université Côte d'Azur ( UCA ) -Centre National de la Recherche Scientifique ( CNRS ), Centre de Recherche en Cancérologie / Nantes - Angers ( CRCNA ), CHU Angers-Centre hospitalier universitaire de Nantes ( CHU Nantes ) -Hôtel-Dieu de Nantes-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Hôpital Laennec-Centre National de la Recherche Scientifique ( CNRS ) -Faculté de Médecine d'Angers, OSE Immunotherapeutics [Nantes], Immunité et cancer ( U932 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut Curie-Institut National de la Santé et de la Recherche Médicale ( INSERM ), ANR-10-IBHU-0005/10-IBHU-0005,CESTI (TSI-IHU),CESTI (TSI-IHU) ( 2010 ), ANR-11-LABX-0016/11-LABX-0016,IGO,Immunothérapies Grand Ouest ( 2011 ), ANR-10-IDEX-0001-02/10-IDEX-0001,PSL,PSL ( 2010 ), ANR-10-IDEX-0001-02/11-LABX-0043,DCBIOL,Biologie des cellules dendritiques ( 2010 ), Centre de Recherche en Transplantation et Immunologie (U1064 Inserm - CRTI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), University of Maryland School of Medicine, University of Maryland System-University of Maryland System, Immuno-Endocrinologie Cellulaire et Moléculaire [Nantes] (IECM), Institut National de la Recherche Agronomique (INRA)-Université de Nantes (UN)-Ecole Nationale Vétérinaire, Agroalimentaire et de l'alimentation Nantes-Atlantique (ONIRIS), Institut de pharmacologie moléculaire et cellulaire (IPMC), Centre National de la Recherche Scientifique (CNRS)-Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Université Côte d'Azur (UCA), Centre de Recherche en Cancérologie Nantes-Angers (CRCNA), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM)-Hôtel-Dieu de Nantes-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital Laennec-Centre National de la Recherche Scientifique (CNRS)-Faculté de Médecine d'Angers-Centre hospitalier universitaire de Nantes (CHU Nantes), Immunité et cancer (U932), Université Paris Descartes - Paris 5 (UPD5)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Fondation Progreffe, JDRF [5-2010-640], IMBIO network, Region Pays de la Loire, IHU-Cesti project, Investissements d'Avenir French, ANR-10-IBHU-0005,CESTI (TSI-IHU),Centre Européen des Sciences de la Transplantation et de l'Immunothérapie (TSI-IHU)(2010), ANR-11-LABX-0016,IGO,Immunothérapies Grand Ouest(2011), ANR-10-IDEX-0001,PSL,Paris Sciences et Lettres(2010), Université Nice Sophia Antipolis (... - 2019) (UNS), Université Côte d'Azur (UCA)-Université Côte d'Azur (UCA)-Centre National de la Recherche Scientifique (CNRS), Centre de Recherche en Cancérologie / Nantes - Angers (CRCNA), Centre hospitalier universitaire de Nantes (CHU Nantes)-Faculté de Médecine d'Angers-Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM)-Centre National de la Recherche Scientifique (CNRS)-Hôpital Laennec-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôtel-Dieu de Nantes, Institut Curie-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), ANR-10-IBHU-0005/10-IBHU-0005,CESTI (TSI-IHU),CESTI (TSI-IHU)(2010), ANR-11-LABX-0016/11-LABX-0016,IGO,Immunothérapies Grand Ouest(2011), ANR-10-IDEX-0001-02/10-IDEX-0001,PSL,Paris Sciences et Lettres(2010), ANR-10-IDEX-0001-02/11-LABX-0043,DCBIOL,Biologie des cellules dendritiques(2010), Bernardo, Elizabeth, Instituts Hospitalo-Universitaires B - Centre Européen des Sciences de la Transplantation et de l'Immunothérapie (TSI-IHU) - - CESTI (TSI-IHU)2010 - ANR-10-IBHU-0005 - IBHU - VALID, Laboratoires d'excellence - Immunothérapies Grand Ouest - - IGO2011 - ANR-11-LABX-0016 - LABX - VALID, Initiative d'excellence - Paris Sciences et Lettres - - PSL2010 - ANR-10-IDEX-0001 - IDEX - VALID, Immuno-Endocrinologie Cellulaire et Moléculaire (IECM), Institut National de la Recherche Agronomique (INRA)-Université de Nantes (UN)-Ecole Nationale Vétérinaire de Nantes-École nationale vétérinaire, agroalimentaire et de l'alimentation Nantes-Atlantique (ONIRIS), Université Nice Sophia Antipolis (1965 - 2019) (UNS), and COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA)

Subjects
CD4-Positive T-Lymphocytes, 0301 basic medicine, T-lymphocyte, Chemokine, T-Lymphocytes, T cell, Immunology, Antigen-Presenting Cells, Mice, Transgenic, T-Cell Antigen Receptor Specificity, [SDV.CAN]Life Sciences [q-bio]/Cancer, Autoimmunity, Autoantigens, Autoimmune Diseases, [ SDV.CAN ] Life Sciences [q-bio]/Cancer, Mice, 03 medical and health sciences, [SDV.CAN] Life Sciences [q-bio]/Cancer, Antigen, medicine, Animals, Humans, Immunology and Allergy, Hypersensitivity, Delayed, Intradermal injection, Antigens, Migration, biology, Effector, Diabetes, Dendritic cell, Papio anubis, Auto-immune encephalomyelitis, Delayed type hypersensitivity, 3. Good health, Heme oxygenase, 030104 developmental biology, medicine.anatomical_structure, Gene Expression Regulation, Heme oxygenase-1, biology.protein, Cytokines, Immunization, Myelin-Oligodendrocyte Glycoprotein, Tolerance, Monocyte-derived dendritic cells, CD8, T-Lymphocytes, Cytotoxic
Abstract

International audience; Developing protocols aimed at inhibiting effector T cells would be key for the treatment of T cell-dependent autoimmune diseases including type 1 autoimmune diabetes (T1D) and multiple sclerosis (MS). While heme oxygenase-1 (HO-1) inducers are clinically approved drugs for non-immune-related diseases, they do have immunosuppressive properties when administered systemically in rodents. Here we show that HO-1 inducers inhibit antigen-specific effector T cells when injected intradermally together with the T cell cognate antigens in mice. This phenomenon was observed in both a CD8 þ T cell-mediated model of T1D and in a CD4 þ T cell-dependent MS model. Intradermal injection of HO-1 in-ducers induced the recruitment of HO-1 þ monocyte-derived dendritic cell (MoDCs) exclusively to the lymph nodes (LN) draining the site of intradermal injection. After encountering HO-1 þ MoDCs, effector T-cells exhibited a lower velocity and a reduced ability to migrate towards chemokine gradients resulting in impaired accumulation to the inflamed organ. Intradermal co-injection of a clinically approved HO-1 inducer and a specific antigen to non-human primates also induced HO-1 þ MoDCs to accumulate in dermal draining LN and to suppress delayed-type hypersensitivity. Therefore, in both mice and non-human primates, HO-1 inducers delivered locally inhibited effector T-cells in an antigen-specific manner, paving the way for repositioning these drugs for the treatment of immune-mediated diseases.

Published
2017

2. Peripheral CD8 effector-memory type 1 T-cells correlate with outcome in ipilimumab-treated stage IV melanoma patients

Author

Christian U. Blank, Michele Maio, Michael A. Postow, Benjamin Weide, Phillip Wong, Dirk Schadendorf, Anna Maria Di Giacomo, Florian Heubach, Jianda Yuan, Paolo A. Ascierto, Amir Khammari, Marnix H Geukes Foppen, Brigitte Dréno, Graham Pawelec, Claus Garbe, Emanuela Romano, Domenico Mallardo, Bastian Schilling, Jedd D. Wolchok, Kilian Wistuba-Hamprecht, Alexander Martens, Department of Dermatology [Tubingen, Germany], University Medical Center [Tubingen, Germany], Department of Internal Medicine II [Tübingen, Germany], University Medical Center [Tübingen, Germany], Immunité et cancer (U932), Université Paris Descartes - Paris 5 (UPD5)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), The Netherlands Cancer Institute [Amsterdam, The Netherlands], Memorial Sloane Kettering Cancer Center [New York], Weill Medical College of Cornell University [New York], Istituto Nazionale Tumori Fondazione Pascale [Naples, Italy], Department of Dermatology [Essen, Germany], University Hospital [Essen, Germany]-West German Cancer Center [Essen, Germany]-University Duisburg-Essen [Germany], German Cancer Consortium [Heidelberg] (DKTK), Division of Medical Oncology and Immunotherapy [Siena, Italy], University Hospital of Siena, Centre de Recherche en Cancérologie Nantes-Angers (CRCNA), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM)-Hôtel-Dieu de Nantes-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital Laennec-Centre National de la Recherche Scientifique (CNRS)-Faculté de Médecine d'Angers-Centre hospitalier universitaire de Nantes (CHU Nantes), School of Science and Technology [Nottingham, U.K.], Nottingham Trent University, Division of Cancer Studies [London, UK], King‘s College London, Parts of this study were funded by Bristol-Myers Squibb (Munich, Germany) to B Weide. Parts of this study were funded by the EU Seventh Framework Program ‘PRIAT’ (Profiling Responders In Antibody Therapies) grant agreement no 305309 to C Garbe. Parts of this study were funded by Deutsche Forschungsgemeinschaft DFG PA 361-22/1 to G. Pawelec., European Project: 305309,EC:FP7:HEALTH,FP7-HEALTH-2012-INNOVATION-1,PRIAT(2012), Bernardo, Elizabeth, Profiling Responders In Antibody Therapies - PRIAT - - EC:FP7:HEALTH2012-11-01 - 2014-10-31 - 305309 - VALID, Immunité et cancer ( U932 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut Curie-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Memorial Sloan Kettering Cancer Center [New York, NY, USA], Weill Cornell Medical College [New York, NY, USA], German Cancer Consortium - DKTK [Heidelberg, Germany], Centre de Recherche en Cancérologie / Nantes - Angers ( CRCNA ), CHU Angers-Hôtel-Dieu de Nantes-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Hôpital Laennec-Centre National de la Recherche Scientifique ( CNRS ) -Faculté de Médecine d'Angers-Centre hospitalier universitaire de Nantes ( CHU Nantes ), Nottingham Trent University [U.K.], European Project : 305309,EC:FP7:HEALTH,FP7-HEALTH-2012-INNOVATION-1,PRIAT ( 2012 ), and Universität Duisburg-Essen = University of Duisburg-Essen [Essen]-University Hospital [Essen, Germany]-West German Cancer Center [Essen, Germany]

Subjects
CD4-Positive T-Lymphocytes, Male, 0301 basic medicine, Oncology, Cancer Research, Skin Neoplasms, Programmed Cell Death 1 Receptor, Medizin, Kaplan-Meier Estimate, CD8-Positive T-Lymphocytes, [ SDV.CAN ] Life Sciences [q-bio]/Cancer, 0302 clinical medicine, Biomarker, Effector memory cells, Ipilimumab, Melanoma, Prognosis, medicine.diagnostic_test, Effector, Antibodies, Monoclonal, Middle Aged, Flow Cytometry, Peripheral, 030220 oncology & carcinogenesis, Biomarker (medicine), Female, medicine.drug, Adult, medicine.medical_specialty, Antineoplastic Agents, [SDV.CAN]Life Sciences [q-bio]/Cancer, Peripheral blood mononuclear cell, Article, Flow cytometry, 03 medical and health sciences, [SDV.CAN] Life Sciences [q-bio]/Cancer, Antigens, Neoplasm, Internal medicine, Biomarkers, Tumor, medicine, Humans, Aged, business.industry, medicine.disease, 030104 developmental biology, Immunology, business, Immunologic Memory, CD8
Abstract

International audience; The role of the assessment of peripheral T-cell phenotypes in predicting overall survival (OS) after ipilimumab treatment is unclear. Here, we analysed mononuclear cells in the blood before and at different time points during treatment with ipilimumab in 137 late-stage melanoma patients. The proportions of baseline naïve and memory T-cells were measured by flow cytometry and correlated with OS, with an emphasis on PD-1 expression. High frequencies (>13%) of CD8 effector-memory type 1 (EM1) T-cells at baseline correlated with longer OS (p = 0.029) and higher clinical response rates (p = 0.01). The frequency of these EM1 cells and the M category had independent impacts on OS (hazard ratio = 1.5, p = 0.033; and hazard ratio = 1.9, p = 0.007). In contrast, high baseline frequencies of late stage-differentiated effector memory CD8 cells (>23.8%) were negatively associated with OS (p = 0.034) but did not correlate with clinical response. Following treatment, a decrease of CD8 cells from baseline to the time of the second drug dose and at later time points was strongly and consistently correlated with a high clinical response rate. Our observations thus suggest an important predictive role of baseline CD8 EM1 cells and changes in CD8 cells for clinical response of ipilimumab. Further validation of these biomarker candidates is warranted.

Published
2017

3. Contribution of endocrine therapy in oestrogen receptor-positive pT1a-b breast cancer: Results of a retrospective study

Author

Gilles Houvenaeghel, Alexandre de Nonneville, Monique Cohen, Jean-Marc Classe, Fabien Reyal, Chafika Mazouni, Christelle Faure, Alejandra Martinez, Marie-Pierre Chauvet, Emile Daraï, Charles Coutant, Pierre-Emmanuel Colombo, Pierre Gimbergues, Anne-Sophie Azuar, Roman Rouzier, Christine Tunon de Lara, Patrice Crochet, Sandrine Rua, Anthony Gonçalves, Centre de Recherche en Cancérologie de Marseille (CRCM), Aix Marseille Université (AMU)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), Sciences Economiques et Sociales de la Santé & Traitement de l'Information Médicale (SESSTIM - U1252 INSERM - Aix Marseille Univ - UMR 259 IRD), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Département de Chirurgie Oncologique [Institut Paoli-Calmettes, Marseille], Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), Institut de Cancérologie de l'Ouest [Angers/Nantes] (UNICANCER/ICO), UNICANCER, Département de chirurgie, Institut Curie [Paris], CRLCC Jean Godinot, Residual Tumor & Response to Treatment Laboratory [Paris] (RT2Lab), Immunité et cancer (U932), Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Gustave Roussy (IGR), Centre de Recherches en Cancérologie de Toulouse (CRCT), Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre Régional de Lutte contre le Cancer Oscar Lambret [Lille] (UNICANCER/Lille), Université de Lille-UNICANCER, Centre de Recherche Saint-Antoine (CRSA), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), Institut du Cancer de Montpellier (ICM), Centre Jean Perrin [Clermont-Ferrand] (UNICANCER/CJP), Hopital de Grasse, Cancer et génome: Bioinformatique, biostatistiques et épidémiologie d'un système complexe, Mines Paris - PSL (École nationale supérieure des mines de Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Département d'oncologie chirurgicale, Centre Régional de Lutte contre le Cancer François Baclesse [Caen] (UNICANCER/CRLC), Normandie Université (NU)-UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU)-UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN), Normandie Université (NU)-UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN), Department of Obstetrics and Gynecology, Assistance Publique H^opitaux de Marseille, La Conception Hospital, 13005 Marseille, Aix Marseille University, France, and Aix Marseille Université (AMU)

Subjects
Cancer Research, Receptors, Estrogen, Oncology, Chemotherapy, Adjuvant, Receptor, ErbB-2, [SDV]Life Sciences [q-bio], Humans, Female, Breast Neoplasms, Disease-Free Survival, Retrospective Studies
Abstract

Introduction: Few data have been reported regarding endocrine therapy (ET) in patients with small pT1a-b ER-postive breast cancer (BC). Thus, we conducted a study to detect possible survival improvements due to ET in such patients. Methods: Our retrospective observational study included 5545 patients with pT1a-b ERpositive BC treated in 15 French centres, excluding patients with HER2-positive status, neoadjuvant chemotherapy, ER-negative status, unknown pN status or in situ BC. We estimated disease-free survival (DFS), recurrence-free survival (RFS) and overall survival (OS) via univariate analysis and multivariate Cox regression. Results: Most patients (80.3%: 4453) received ET and-when compared to those without ET -experienced increases of 2.5% and 3.3% in DFS and 1.9% and 4.3% in RFS after 5 and 7 years of follow-up, respectively, with little difference in OS. In Cox regression analysis, no ET was significantly associated with decreased DFS (hazard ratio, HR = 1.275, p = 0.047, 95% CI[1.003-1.620]) but not OS or RFS in all patients, while in 2363 patients with pT1ab ER-positive grade 2-3 BC, no ET was significantly associated with decreased DFS (HR = 1.502, p = 0.049, 95% CI[1.001-2.252]), but not OS (HR = 1.361, p = 0.272). ET omission was not significantly associated with decreased survival in 3047 patients with pT1a-b ER-positive grade 1 BC. Conclusion: Our results indicate that while ET provided a beneficial impact on survival to patients with pT1a-bN0 ER-positive BC-and especially in those with grade 2-3 tumours-no such impact was observed in grade 1 tumours. Consequently, ET should be discussed with these patients, particularly in those with pT1a grade 1 tumours. 2022 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Published
2022

4. Mutant Mice Lacking the p53 C-Terminal Domain Model Telomere Syndromes

Author

Sara Jaber, Ming Fang, Michel Huerre, Boris Bardot, Laure Charbonnier, Claire Soudais, Franck Toledo, Rachida Bouarich-Bourimi, Jean-Christophe Bourdon, Iva Simeonova, Irena Draskovic, Vincent Lejour, Arturo Londoño-Vallejo, Dynamique de l'information génétique : bases fondamentales et cancer (DIG CANCER), Centre National de la Recherche Scientifique (CNRS)-Institut Curie [Paris]-Université Pierre et Marie Curie - Paris 6 (UPMC), Université Pierre et Marie Curie - Paris 6 (UPMC), Immunité et cancer (U932), Université Paris Descartes - Paris 5 (UPD5)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), CD4+T-Lymphocytes and Anti-Tumour Response, University of Dundee, Département de Pathologie [Curie], Institut Curie [Paris], HAL UPMC, Gestionnaire, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut Curie [Paris]-Centre National de la Recherche Scientifique (CNRS), Dynamique de l'information génétique : bases fondamentales et cancer ( DIG CANCER ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -INSTITUT CURIE-Centre National de la Recherche Scientifique ( CNRS ), Telomeres and Cancer Laboratory, INSTITUT CURIE, Immunité et cancer ( U932 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Institut Curie, and Institut Curie

Subjects
Male, Telomere-Binding Proteins, Mutant, Gene Expression, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biology, TINF2, medicine.disease_cause, General Biochemistry, Genetics and Molecular Biology, Dyskerin, [ SDV.CAN ] Life Sciences [q-bio]/Cancer, Mice, 03 medical and health sciences, 0302 clinical medicine, [SDV.CAN] Life Sciences [q-bio]/Cancer, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Pulmonary fibrosis, medicine, Animals, Humans, Aplastic anemia, lcsh:QH301-705.5, 030304 developmental biology, 0303 health sciences, Mutation, Syndrome, Telomere, medicine.disease, Mice, Mutant Strains, Protein Structure, Tertiary, 3. Good health, Disease Models, Animal, lcsh:Biology (General), [ SDV.BBM.GTP ] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], 030220 oncology & carcinogenesis, Cancer research, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Tumor Suppressor Protein p53, Dyskeratosis congenita
Abstract

International audience; Mutations in p53, although frequent in human cancers , have not been implicated in telomere-related syndromes. Here, we show that homozygous mutant mice expressing p53 D31 , a p53 lacking the C-terminal domain, exhibit increased p53 activity and suffer from aplastic anemia and pulmonary fibrosis, hallmarks of syndromes caused by short telomeres. Indeed, p53 D31/D31 mice had short telomeres and other phenotypic traits associated with the telomere disease dyskeratosis congenita and its severe variant the Hoyeraal-Hreidarsson syndrome. Hetero-zygous p53 +/D31 mice were only mildly affected, but decreased levels of Mdm4, a negative regulator of p53, led to a dramatic aggravation of their symptoms. Importantly, several genes involved in telomere metabolism were downregulated in p53 D31/D31 cells, including Dyskerin, Rtel1, and Tinf2, which are mutated in dyskeratosis congenita, and Terf1, which is implicated in aplastic anemia. Together, these data reveal that a truncating mutation can activate p53 and that p53 plays a major role in the regulation of telomere metabolism.

Published
2013
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5. X-linked primary immunodeficiency associated with hemizygous mutations in the moesin (MSN) gene

Author

Jacek Majewski, Marielle E. van Gijn, Alain Fischer, Geneviève de Saint Basile, Capucine Picard, Nada Jabado, Els Verhoeyen, Sonia Luce, Tayebeh Soheili, Nathalie Lambert, Amandine Durand, Armelle Bohineust, Claire Hivroz, Virginie Gandemer, Farid Ouchani, Chantal Brouzes, Catherine Heijmans, Anne Durandy, Isabelle Pic, Myriam Chouteau, Marina Cavazzana, Virgil A. S. H. Dalm, Nizar Mahlaoui, Aude Magerus-Chatinet, François-Loïc Cosset, Isabelle André-Schmutz, Delphine Monnier, Sven Kracker, Chantal Lagresle-Peyrou, Jean-Louis Stephan, Frédéric Rieux-Laucat, Hanem Sadek, Human Lymphohematopoiesis Laboratory (Equipe Inserm U1163), Imagine - Institut des maladies génétiques (IMAGINE - U1163), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Département de Biothérapie [CHU Necker], CHU Necker - Enfants Malades [AP-HP]-Université Paris Descartes - Paris 5 (UPD5)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), McGill University and Genome Quebec Innovation Centre, CHU Necker - Enfants Malades [AP-HP], Center for the Study of Primary Immunodeficiencies [Paris], Université Paris Descartes - Paris 5 (UPD5)-CHU Necker - Enfants Malades [AP-HP], Immunité et cancer (U932), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Curie-Université Paris Descartes - Paris 5 (UPD5), Centre méditerranéen de médecine moléculaire (C3M), Université Nice Sophia Antipolis (... - 2019) (UNS), Université Côte d'Azur (UCA)-Université Côte d'Azur (UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Virus enveloppés, vecteurs et immunothérapie – Enveloped viruses, Vectors and Immuno-therapy (Equipe EVIR), Centre International de Recherche en Infectiologie - UMR (CIRI), École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Immunogenetics of pediatric autoimmune diseases (Equipe Inserm U1163), Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), CHU Pontchaillou [Rennes], Service d'Hématologie, Immunologie et de Thérapie Cellulaire (HITC), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Hôpital Pontchaillou-CHU Pontchaillou [Rennes], Hôpital Universitaire des Enfants - Reine Fabiola, Dpt of Genetics [Utrecht], University Medical Center [Utrecht], Department of Internal Medicine, Erasmus University Medical Center [Rotterdam] (Erasmus MC), Centre de Référence Déficits Immunitaires Héréditaires (CEREDIH), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Necker - Enfants Malades [AP-HP], Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'immuno-hématologie pédiatrique [CHU Necker], CHU Saint-Etienne, the Genome Quebec Innovation Centre, McGill University, Collège de France (CdF), French National Research Agency, French National Institute of Health and Medical Research (INSERM), La Ligue contre le Cancer and La Fondation ARC pour la Recherche sur le Cancer, Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Descartes - Paris 5 (UPD5)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Paris Descartes - Paris 5 (UPD5)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Nice Sophia Antipolis (1965 - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Côte d'Azur (UCA), Virus enveloppés, vecteurs et immunothérapie – Enveloped viruses, Vectors and Immuno-therapy (EVIR), Centre International de Recherche en Infectiologie (CIRI), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Université de Rennes (UR)-Hôpital Pontchaillou-CHU Pontchaillou [Rennes], Hôpital Universitaire des Enfants Reine Fabiola [Bruxelles, Belgique] (HUDERF), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne] (CHU ST-E), McGill University = Université McGill [Montréal, Canada], Collège de France - Chaire Médecine expérimentale (A. Fischer), Collège de France (CdF (institution)), Imagine - Institut des maladies génétiques ( IMAGINE - U1163 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), CIC-BT 502 INSERM, Departement de Biotherapie, Laboratoire d'hématologie ( ERL 8254 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Centre de Référence Déficits Immunitaires Héréditaires ( CEREDIH ), Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Immunité et cancer ( U932 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut Curie-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Centre méditérannéen de médecine moléculaire ( C3M ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Nice Sophia Antipolis ( UNS ), Université Côte d'Azur ( UCA ) -Université Côte d'Azur ( UCA ), Centre International de Recherche en Infectiologie ( CIRI ), École normale supérieure - Lyon ( ENS Lyon ) -Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Institut de Génétique et Développement de Rennes ( IGDR ), Université de Rennes 1 ( UR1 ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -Centre National de la Recherche Scientifique ( CNRS ) -Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Service d'Hématologie, Immunologie et de Thérapie Cellulaire ( HITC ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -Hôpital Pontchaillou-CHU Pontchaillou [Rennes], Collège de France ( CdF ), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Descartes - Paris 5 (UPD5), Institut National de la Santé et de la Recherche Médicale (INSERM)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Chaire Médecine expérimentale (A. Fischer), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Université Paris Descartes - Paris 5 (UPD5)-CHU Necker - Enfants Malades [AP-HP], Institut Curie-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Immunology, and Internal Medicine

Subjects
Adult, Male, 0301 basic medicine, Adolescent, Moesin, Immunology, Nonsense mutation, macromolecular substances, CD8-Positive T-Lymphocytes, Biology, Infections, primary immunodeficiency, migration, medicine.disease_cause, ezrin-radixin-moesin protein, Hypogammaglobulinemia, 03 medical and health sciences, Cell Movement, Radixin, Cell Adhesion, Journal Article, medicine, Humans, Immunology and Allergy, Missense mutation, Lymphocyte Count, Child, moesin, Genetic Association Studies, Immunodeficiency, Aged, Chromosomes, Human, X, [SDV.GEN]Life Sciences [q-bio]/Genetics, Mutation, Microfilament Proteins, Immunologic Deficiency Syndromes, Leukopenia, medicine.disease, Pedigree, 3. Good health, adhesion, 030104 developmental biology, Child, Preschool, Cancer research, Primary immunodeficiency, [ SDV.GEN ] Life Sciences [q-bio]/Genetics
Abstract

International audience; BACKGROUND: We investigated 7 male patients (from 5 different families) presenting with profound lymphopenia, hypogammaglobulinemia, fluctuating monocytopenia and neutropenia, a poor immune response to vaccine antigens, and increased susceptibility to bacterial and varicella zoster virus infections. OBJECTIVE: We sought to characterize the genetic defect involved in a new form of X-linked immunodeficiency. METHODS: We performed genetic analyses and an exhaustive phenotypic and functional characterization of the lymphocyte compartment. RESULTS: We observed hemizygous mutations in the moesin (MSN) gene (located on the X chromosome and coding for MSN) in all 7 patients. Six of the latter had the same missense mutation, which led to an amino acid substitution (R171W) in the MSN four-point-one, ezrin, radixin, moesin domain. The seventh patient had a nonsense mutation leading to a premature stop codon mutation (R533X). The naive T-cell counts were particularly low for age, and most CD8(+) T cells expressed the senescence marker CD57. This phenotype was associated with impaired T-cell proliferation, which was rescued by expression of wild-type MSN. MSN-deficient T cells also displayed poor chemokine receptor expression, increased adhesion molecule expression, and altered migration and adhesion capacities. CONCLUSION: Our observations establish a causal link between an ezrin-radixin-moesin protein mutation and a primary immunodeficiency that could be referred to as X-linked moesin-associated immunodeficiency.

Published
2016

6. Antigen presentation by mouse monocyte-derived cells: Re-evaluating the concept of monocyte-derived dendritic cells

Author

Elodie Segura, Alice Coillard, Immunité et cancer (U932), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Curie [Paris], Université Paris sciences et lettres (PSL), and Segura, Elodie

Subjects
0301 basic medicine, monocyte-derived dendritic cell, T-Lymphocytes, Immunology, Population, Antigen presentation, Inflammation, Biology, Lymphocyte Activation, [SDV.IMM.II]Life Sciences [q-bio]/Immunology/Innate immunity, Monocytes, Mice, 03 medical and health sciences, 0302 clinical medicine, Antigen, medicine, Animals, Antigens, education, [SDV.IMM.II] Life Sciences [q-bio]/Immunology/Innate immunity, Molecular Biology, education.field_of_study, Effector, Monocyte, Cell Differentiation, Dendritic Cells, Dendritic cell, Phenotype, Cell biology, antigen presentation, 030104 developmental biology, medicine.anatomical_structure, [SDV.IMM.IA]Life Sciences [q-bio]/Immunology/Adaptive immunology, inflammation, [SDV.IMM.IA] Life Sciences [q-bio]/Immunology/Adaptive immunology, monocyte, medicine.symptom, 030215 immunology
Abstract

International audience; Antigen presentation is a key feature of classical dendritic cells (cDCs). Numerous studies have also reported in mouse that, upon inflammation, monocytes enter tissues and differentiate into monocyte-derived DCs (mo-DC) that have the ability to present antigens to T cells. However, a population of inflammatory cDCs sharing phenotypic features with mo-DC has been recently described, challenging the existence of in vivo-generated mo-DC. Here we review studies describing mouse mo-DC in the light of these findings, and evaluate the in vivo evidence for monocyte-derived antigen-presenting cells. We examine the strategies used to demonstrate the monocytic origin of these cells. Finally, we propose that mo-DC play a complementary role to cDCs, by presenting antigens to effector T cells locally in tissues.

Published
2021

7. Associations between consumption of dietary fibers and the risk of cardiovascular diseases, cancers, type 2 diabetes, and mortality in the prospective NutriNet-Santé cohort

Author

Elisa Desmetz, Lluis Quintana-Murci, Mathilde Touvier, Léopold Fezeu, Serge Hercberg, Nathalie Druesne-Pecollo, Chantal Julia, Darragh Duffy, Pilar Galan, Mélanie Deschasaux, Paule Latino-Martel, Valentin Partula, Olivier Lantz, Bernard Srour, Stanislas Mondot, Emmanuelle Kesse-Guyot, Eloi Chazelas, Matthew L. Albert, Equipe 3: EREN- Equipe de Recherche en Epidémiologie Nutritionnelle (CRESS - U1153), Université Sorbonne Paris Nord-Centre de Recherche Épidémiologie et Statistique Sorbonne Paris Cité (CRESS (U1153 / UMR_A_1125 / UMR_S_1153)), Conservatoire National des Arts et Métiers [CNAM] (CNAM), HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Conservatoire National des Arts et Métiers [CNAM] (CNAM), HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Université Paris Cité (UPCité), Hôpital Avicenne [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), MICrobiologie de l'ALImentation au Service de la Santé (MICALIS), AgroParisTech-Université Paris-Saclay-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Immunité et cancer (U932), Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), CIC1428 IGR-CURIE, Génétique Evolutive Humaine - Human Evolutionary Genetics, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Chaire Génomique humaine et évolution, Collège de France (CdF (institution)), Department of Immunology and Infectious Diseases, Insitro [San Francisco], Immunobiologie des Cellules dendritiques, Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), NutriNet-Santé study was supported by the following French public institutions: Ministère de la Santé, Santé Publique France, Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Recherche Agronomique (INRA), Conservatoire National des Arts et Métiers (CNAM) and Université Paris-XIII Nord. The Milieu Intérieur Consortium was supported by French Government’s Investissement d’Avenir Program, Laboratoire d’Excellence 'Milieu Intérieur' Grant ANR-10-LABX-69-01. Valentin Partula was funded by Ph.D. a grant from the Labex Milieu Interieur, and is provided financial support from École doctorale 474 Frontières de l’Innovation en Recherche et Education – Programme Bettencourt., Milieu intérieur, ANR-10-LABX-0069,MILIEU INTERIEUR,GENETIC & ENVIRONMENTAL CONTROL OF IMMUNE PHENOTYPE VARIANCE: ESTABLISHING A PATH TOWARDS PERSONALIZED MEDICINE(2010), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Collège de France - Chaire Génomique humaine et évolution, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Conservatoire National des Arts et Métiers [CNAM] (CNAM)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Conservatoire National des Arts et Métiers [CNAM] (CNAM)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Université de Paris (UP), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Curie [Paris]

Subjects
Adult, Dietary Fiber, Male, medicine.medical_specialty, Colorectal cancer, prospective cohort, Medicine (miscellaneous), 030209 endocrinology & metabolism, Type 2 diabetes, dietary fibers, 03 medical and health sciences, 0302 clinical medicine, Breast cancer, Neoplasms, Internal medicine, Vegetables, cancers, medicine, Humans, Prospective Studies, 030212 general & internal medicine, Prospective cohort study, 2. Zero hunger, Nutrition and Dietetics, Proportional hazards model, business.industry, Public health, Cancer, Middle Aged, medicine.disease, mortality, cardiovascular diseases, 3. Good health, Diabetes Mellitus, Type 2, Fruit, Cohort, [SDV.IMM]Life Sciences [q-bio]/Immunology, Female, type 2 diabetes, business
Abstract

BACKGROUND Mounting evidence, yet with varying levels of proof, suggests that dietary fibers (DFs) may exert a protective role against various chronic diseases, but this might depend on the DF type and source. OBJECTIVES Our objectives were to assess the associations between the intake of DFs of different types [total (TDF), soluble (SF), insoluble (IF)] and from different sources (fruits, vegetables, whole grains, legumes, potatoes and tubers) and the risk of cardiovascular diseases (CVDs), cancer, type 2 diabetes (T2D), and mortality in the large-scale NutriNet-Sante prospective cohort (2009-2019). METHODS Overall, 107,377 participants were included. Usual DF intake was estimated from validated repeated 24-h dietary records over the first 2 y following inclusion in the cohort. Associations between sex-specific quintiles of DF intake and the risk of chronic diseases and mortality were assessed using multiadjusted Cox proportional hazards models. RESULTS T2D risk was inversely associated with TDFs [HR for quintile 5 compared with quintile 1: 0.59 (95% CI: 0.42, 0.82), P-trend

Published
2020

8. Immunopathological manifestations in Kabuki syndrome: a registry study of 177 individuals

Author

Margot, Henri, Boursier, Guilaine, Duflos, Claire, Sanchez, Elodie, Amiel, Jeanne, Andrau, Jean-Christophe, Arpin, Stéphanie, Brischoux-Boucher, Elise, Boute, Odile, Burglen, Lydie, Caille, Charlotte, Capri, Yline, Collignon, Patrick, Conrad, Solène, CORMIER-DAIRE, Valerie, Delplancq, Geoffroy, Dieterich, Klaus, Dollfus, Hélène, Fradin, Mélanie, Faivre, Laurence, Fernandes, Helder, Francannet, Christine, Gatinois, Vincent, Gérard, Marion, Goldenberg, Alice, Ghoumid, Jamal, Grotto, Sarah, Guerrot, Anne-Marie, Guichet, Agnès, Isidor, Bertrand, Jacquemont, Marie-Line, Julia, Sophie, Philip, K, Legendre, Marine, Le Quan Sang, K., Leheup, Bruno, Lyonnet, Stanislas, Magry, Virginie, Manouvrier, Sylvie, Martin, Dominique, Morel, Godelieve, Munnich, Arnold, Naudion, Sophie, Odent, Sylvie, Perrin, Laurence, Petit, Florence, Philip, Nicole, Rio, Marlène, Robbe, Julie, Rossi, Massimiliano, Sarrazin, Elisabeth, Toutain, Annick, Van Gils, Julien, Vera, Gabriella, Verloes, Alain, Weber, Sacha, Whalen, Sandra, Sanlaville, Damien, Lacombe, Didier, Aladjidi, Nathalie, Geneviève, David, Khau Van Kien, Philippe, Van Gils, Julie, Service de génétique médicale, Université de Bordeaux (UB)-CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, Physiologie & médecine expérimentale du Cœur et des Muscles [U 1046] (PhyMedExp), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Cellules Souches, Plasticité Cellulaire, Médecine Régénératrice et Immunothérapies (IRMB), Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Université Paris Descartes - Paris 5 (UPD5), Centre d'Immunologie de Marseille - Luminy (CIML), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service de génétique [Tours], Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)-Hôpital Bretonneau, Service de Génétique clinique, Hôpital Jeanne de Flandre [Lille]-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Hôpital Robert Debré Paris, Hôpital Robert Debré, Service de Génétique Médicale, Hôpital intercommunal de Font-Pré, Centre hospitalier universitaire de Nantes (CHU Nantes), Génétique et épigénétique des maladies métaboliques, neurosensorielles et du développement (Inserm U781), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Muscle et Pathologies, [GIN] Grenoble Institut des Neurosciences (GIN), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes (UGA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes (UGA), Centre de Référence pour les Affections Rares en Génétique Ophtalmologique (CARGO) et Service de Génétique Médicale, Hôpitaux Universitaires de Strasbourg, CLAD Ouest, Centre Hospitalier Universitaire [Rennes], Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), UNICANCER, Service de Génétique Médicale [CHU Clermont-Ferrand], CHU Estaing [Clermont-Ferrand], CHU Clermont-Ferrand-CHU Clermont-Ferrand, Service de génétique [Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), Service de génétique clinique, Institut Jacques Monod (IJM (UMR_7592)), Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Service de génétique médicale - Unité de génétique clinique [Nantes], Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes), Centre Hospitalier Universitaire de La Réunion (CHU La Réunion), Service de génétique médicale [Toulouse], CHU Toulouse [Toulouse]-Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse], CHU Bordeaux [Bordeaux], Service de Médecine Infantile III et Génétique Clinique [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire des Maladies Rénales Héréditaires, Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital Jeanne de Flandres, Université de Lille, Droit et Santé-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Laboratoire de génétique médicale et cytogénétique [Le Mans], Centre Hospitalier Le Mans (CH Le Mans), Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), AP-HP Hôpital universitaire Robert-Debré [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Lille Neurosciences & Cognition - U 1172 (LilNCog (ex-JPARC)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Service de Génétique, Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), Hydrosciences Montpellier (HSM), Institut national des sciences de l'Univers (INSU - CNRS)-Institut de Recherche pour le Développement (IRD)-Université Montpellier 2 - Sciences et Techniques (UM2)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Centre de recherche en neurosciences de Lyon (CRNL), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre de référence car i b é en des maladies rares neuromusculaires et neurologiques adultes et enfant (CERCA), Hôpital Pierre Zobda Quitman-CHU Fort-de-France, U 1211 Laboratoire Maladies Rares: Génétique et Métabolisme (Bordeaux) (MRGM), Immunité et cancer (U932), Université Paris Descartes - Paris 5 (UPD5)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Physiopathologie et neuroprotection des atteintes du cerveau en développement, Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire régional de télédétection, Institut de Recherche pour le Développement (IRD), Service de Génétique Cytogénétique et Embryologie [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service d'Hémato-oncologie Pédiatrique, CHU Bordeaux [Bordeaux]-Hôpital Pellegrin, Département de génétique médicale, maladies rares et médecine personnalisée [CHRU Montpellier], Laboratoire de génétique des maladies rares. Pathologie moleculaire, etudes fonctionnelles et banque de données génétiques (LGMR), Université Montpellier 1 (UM1)-IFR3, Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), AOM 07-090, Ministère de la Santé et des Services sociaux, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Service Génétique Médicale [CHU Toulouse], Institut Fédératif de Biologie (IFB), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Pôle Biologie [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Lille Neurosciences & Cognition - U 1172 (LilNCog), Institut de Recherche pour le Développement (IRD)-Institut national des sciences de l'Univers (INSU - CNRS)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Centre de recherche en neurosciences de Lyon - Lyon Neuroscience Research Center (CRNL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), gerard, marion, Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU), and Hôpital Bretonneau-Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)

Subjects
Male, [SDV.GEN] Life Sciences [q-bio]/Genetics, Vitiligo, Severity of Illness Index, Hypogammaglobulinemia, 0302 clinical medicine, Prevalence, Medicine, KDM6A, Registries, Child, [SDV.BDD]Life Sciences [q-bio]/Development Biology, ComputingMilieux_MISCELLANEOUS, Genetics (clinical), Immunodeficiency, Histone Demethylases, 0303 health sciences, Genetic disorder, KMT2D, Middle Aged, Thrombocytopenic purpura, Neoplasm Proteins, 3. Good health, DNA-Binding Proteins, Vestibular Diseases, Child, Preschool, Female, Autoimmune hemolytic anemia, Adult, medicine.medical_specialty, Adolescent, Primary Immunodeficiency Diseases, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, Autoimmune Diseases, Young Adult, 03 medical and health sciences, [SDV.BDD] Life Sciences [q-bio]/Development Biology, Humans, Abnormalities, Multiple, Genetic Association Studies, Aged, 030304 developmental biology, Autoimmune disease, [SDV.GEN]Life Sciences [q-bio]/Genetics, Kabuki syndrome, business.industry, Infant, Newborn, Infant, medicine.disease, Hematologic Diseases, immunity, Dermatology, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Face, Mutation, business, 030217 neurology & neurosurgery
Abstract

Kabuki syndrome (KS) (OMIM 147920 and 300867) is a rare genetic disorder characterized by specific facial features, intellectual disability, and various malformations. Immunopathological manifestations seem prevalent and increase the morbimortality. To assess the frequency and severity of the manifestations, we measured the prevalence of immunopathological manifestations as well as genotype–phenotype correlations in KS individuals from a registry. Data were for 177 KS individuals with KDM6A or KMT2D pathogenic variants. Questionnaires to clinicians were used to assess the presence of immunodeficiency and autoimmune diseases both on a clinical and biological basis. Overall, 44.1% (78/177) and 58.2% (46/79) of KS individuals exhibited infection susceptibility and hypogammaglobulinemia, respectively; 13.6% (24/177) had autoimmune disease (AID; 25.6% [11/43] in adults), 5.6% (10/177) with ≥2 AID manifestations. The most frequent AID manifestations were immune thrombocytopenic purpura (7.3% [13/177]) and autoimmune hemolytic anemia (4.0% [7/177]). Among nonhematological manifestations, vitiligo was frequent. Immune thrombocytopenic purpura was frequent with missense versus other types of variants (p = 0.027). The high prevalence of immunopathological manifestations in KS demonstrates the importance of systematic screening and efficient preventive management of these treatable and sometimes life-threatening conditions.

Published
2020

9. The FDA-approved drug Auranofin has a dual inhibitory effect on SARS-CoV-2 entry and NF-κB signaling

Author

Emmanuel Laplantine, Christine Chable-Bessia, Anne Oudin, Jitendryia Swain, Adèle Soria, Peggy Merida, Manon Gourdelier, Sarra Mestiri, Indira Besseghe, Erwan Bremaud, Aymeric Neyret, Sebastien Lyonnais, Cyril Favard, Philippe Benaroch, Mathieu Hubert, Olivier Schwartz, Maryse Guerin, Anne Danckaert, Elaine Del Nery, Delphine Muriaux, Robert Weil, Centre d'Immunologie et des Maladies Infectieuses (CIMI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Centre d’études des Maladies Infectieuses et Pharmacologie Anti-Infectieuse - [Montpellier] (CEMIPAI), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), Institut de génétique humaine (IGH), Institut de Recherche en Infectiologie de Montpellier (IRIM), BioImaging Cell and Tissue Core Facility (PICT-IBiSA), Institut Curie [Paris], Institut Curie, PSL Research University, INSERM U932., Institut Pasteur [Paris], Virologie (CNRS - UMR3569), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Virus et Immunité - Virus and immunity, Vaccine Research Institute (VRI), Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Research Unit on Cardiovascular and Metabolic Diseases [IHU ICAN], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut de Cardiométabolisme et Nutrition = Institute of Cardiometabolism and Nutrition [CHU Pitié Salpêtrière] (IHU ICAN), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), BioImagerie Photonique – Photonic BioImaging (UTechS PBI), Institut Pasteur [Paris]-Université Paris Cité (UPCité), Immunité et cancer (U932), Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Laplantine, Emmanuel, Développment d'une infrastructure française distribuée coordonnée - - France-BioImaging2010 - ANR-10-INBS-0004 - INBS - VALID, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Research Unit on Cardiovascular and Metabolic Diseases (ICAN), Institut Pasteur [Paris] (IP), Institut Pasteur, UTechS Photonic BioImaging (PBI), a member of the national infrastructure France-BioImaging supported by the French National Research Agency (ANR-10-INBS-04), kindly acknowledges the financial support of the Région Ile-de France (program DIM1Health) and the Institut Pasteur. This study was supported by the CNRS and Montpellier University through a Montpellier Université d’Excellence (MUSE) support, and the French Agency for Research through the Fondation de la Recherche Médicale (ANR COVID19 to DM) and Cancéropôle Ile-de-France (Emergence Grant, to EL)., ANR-10-INBS-0004,France-BioImaging,Développment d'une infrastructure française distribuée coordonnée(2010), Virus et Immunité - Virus and immunity (CNRS-UMR3569), and Vaccine Research Institute [Créteil, France] (VRI)

Subjects
Chemistry, Multidisciplinary, Molecular biology, [SDV]Life Sciences [q-bio], [SDV.BC.BC] Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], Medical biochemistry, [SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], [SDV.SP]Life Sciences [q-bio]/Pharmaceutical sciences, Biochemistry
Abstract

International audience; Patients with severe COVID-19 show an altered immune response that fails to control the viral spread and suffer from exacerbated inflammatory response, which eventually can lead to death. A major challenge is to develop an effective treatment for COVID-19. NF-κB is a major player in innate immunity and inflammatory process. By a high-throughput screening approach, we identified FDA-approved compounds that inhibit the NF-κB pathway and thus dampen inflammation. Among these, we show that Auranofin prevents post-translational modifications of NF-κB effectors and their recruitment into activating complexes in response to SARS-CoV-2 infection or cytokine stimulation. In addition, we demonstrate that Auranofin counteracts several steps of SARS-CoV-2 infection. First, it inhibits a raft-dependent endocytic pathway involved in SARS-CoV-2 entry into host cells; Second, Auranofin alters the ACE2 mobility at the plasma membrane. Overall, Auranofin should prevent SARS-CoV-2 infection and inflammatory damages, offering new opportunities as a repurposable drug candidate to treat COVID-19.

Published
2022

10. Primary T-cell immunodeficiency with immunodysregulation caused by autosomal recessive LCK deficiency

Author

Fabien Touzot, Stéphane Gérart, Sylvain Latour, Isabelle Callebaut, André Veillette, Frédéric Rieux-Laucat, Alain Fischer, Capucine Picard, Sébastien Héritier, Claire Hivroz, Zosia Maciorowski, Clotilde Randriamampita, Nathalie Lambert, Stéphane Blanche, Emmanuel Martin, Pierre Quartier, Despina Moshous, Nicole Brousse, Annick Lim, Jean Soulier, Fabian Hauck, Laboratoire du D eveloppement Normal et Pathologique du Syst eme Immunitaire, Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre de Référence Déficits Immunitaires Héréditaires (CEREDIH), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Régulation Immunitaire et Vaccinologie, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Pathologie cellulaire : aspects moléculaires et viraux / Pathologie et Virologie Moléculaire, Institut Universitaire d'Hématologie (IUH), Université Paris Diderot - Paris 7 (UPD7)-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Centre National de la Recherche Scientifique (CNRS), Flow Cytometry Core Facility, Unite d'Immunologie et H ematologie P ediatrique and iService d'Anatomie et de Cytologie Pathologiques, Service d'Anatomie et de Cytologie Pathologiques, Institut de minéralogie et de physique des milieux condensés (IMPMC), Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Diderot - Paris 7 (UPD7)-Institut de Physique du Globe de Paris (IPG Paris)-Centre National de la Recherche Scientifique (CNRS), Molecular Oncology Research Unit, Immunité et cancer (U932), Université Paris Descartes - Paris 5 (UPD5)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), INSERM 980, Laboratory of Human Genetics of Infectious Disease, Laboratory of Human Genetics of Infectious Disease, Imagine - Institut des maladies génétiques ( IMAGINE - U1163 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Institut Cochin ( UM3 (UMR 8104 / U1016) ), Centre de Référence Déficits Immunitaires Héréditaires ( CEREDIH ), Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Paris-Est Créteil Val-de-Marne - Paris 12 ( UPEC UP12 ), Université Paris Diderot - Paris 7 ( UPD7 ) -Institut Universitaire d'Hématologie ( IUH ), Université Paris Diderot - Paris 7 ( UPD7 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris]-Centre National de la Recherche Scientifique ( CNRS ), Institut de minéralogie et de physique des milieux condensés ( IMPMC ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -IPG PARIS-Université Paris Diderot - Paris 7 ( UPD7 ) -Centre National de la Recherche Scientifique ( CNRS ), Immunité et cancer ( U932 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut Curie-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Université Paris Diderot - Paris 7 (UPD7)-Université Paris Diderot - Paris 7 (UPD7)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Pierre et Marie Curie - Paris 6 (UPMC)-IPG PARIS-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), [Institut Cochin] Departement Infection, immunité, inflammation, Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Centre National de la Recherche Scientifique (CNRS), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Curie-Université Paris Descartes - Paris 5 (UPD5)

Subjects
CD4-Positive T-Lymphocytes, DNA Mutational Analysis, chemistry.chemical_compound, 0302 clinical medicine, recurrent infections, Immunology and Allergy, ComputingMilieux_MISCELLANEOUS, Cells, Cultured, Immunodeficiency, 0303 health sciences, CD28, hemic and immune systems, lymphopenia, autoinflammation, Pedigree, LCK, 3. Good health, Child, Preschool, [SDV.IMM]Life Sciences [q-bio]/Immunology, Female, France, T-Cell Immunodeficiency, Tyrosine kinase, Primary Immunodeficiency Diseases, genetic defect, Immunology, Mutation, Missense, Receptors, Antigen, T-Cell, Genes, Recessive, chemical and pharmacologic phenomena, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Biology, 03 medical and health sciences, SRC tyrosine kinase, medicine, Humans, Genetic Predisposition to Disease, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Calcium Signaling, Kinase activity, T-Lymphocytopenia, Idiopathic CD4-Positive, [ SDV.BBM ] Life Sciences [q-bio]/Biochemistry, Molecular Biology, 030304 developmental biology, Polymorphism, Genetic, T-cell receptor, Immunologic Deficiency Syndromes, Tyrosine phosphorylation, medicine.disease, CD4, chemistry, Lymphocyte Specific Protein Tyrosine Kinase p56(lck), Cancer research, immunodeficiency, T-cell receptor signaling, CD8, 030215 immunology
Abstract

Background Signals emanating from the antigen T-cell receptor (TCR) are required for T-cell development and function. The T lymphocyte–specific protein tyrosine kinase (Lck) is a key component of the TCR signaling machinery. On the basis of its function, we considered LCK a candidate gene in patients with combined immunodeficiency. Objective We identify and describe a child with a T-cell immunodeficiency caused by a homozygous missense mutation of the LCK gene (c.1022T>C) resulting from uniparental disomy. Methods Genetic, molecular, and functional analyses were performed to characterize the Lck deficiency, and the associated clinical and immunologic phenotypes are reported. Results The mutant LCK protein (p.L341P) was weakly expressed with no kinase activity and failed to reconstitute TCR signaling in LCK-deficient T cells. The patient presented with recurrent respiratory tract infections together with predominant early-onset inflammatory and autoimmune manifestations. The patient displayed CD4 + T-cell lymphopenia and low levels of CD4 and CD8 expression on the T-cell surface. The residual T lymphocytes had an oligoclonal T-cell repertoire and exhibited a profound TCR signaling defect, with only weak tyrosine phosphorylation signals and no Ca 2+ mobilization in response to TCR stimulation. Conclusion We report a new form of T-cell immunodeficiency caused by a LCK gene defect, highlighting the essential role of Lck in human T-cell development and responses. Our results also point out that defects in the TCR signaling cascade often result in abnormal T-cell differentiation and functions, leading to an important risk factor for inflammation and autoimmunity.

Published
2012

11. Association of Mycoplasma Hominis and head and neck cancer with unknown primary

Author

B. Berçot, C. Hoffmann, V. Laurence, S. Atallah, Immunité et cancer (U932), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Curie [Paris], Institut Curie [Paris], Université Paris sciences et lettres (PSL), Hopital Saint-Louis [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Paris Diderot - Paris 7 (UPD7), Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), and CCSD, Accord Elsevier

Subjects
Pathology, medicine.medical_specialty, [SDV]Life Sciences [q-bio], Cell, Physical examination, Mycoplasma hominis, Young Adult, 03 medical and health sciences, 0302 clinical medicine, Cervical lymphadenopathy, Squamous cell carcinoma, Mycoplasm, Humans, Medicine, Mycoplasma Infections, 030223 otorhinolaryngology, Pathogen, 16S RNA, biology, medicine.diagnostic_test, Squamous Cell Carcinoma of Head and Neck, business.industry, Head and neck cancer, HPV infection, Induction chemotherapy, medicine.disease, biology.organism_classification, 3. Good health, [SDV] Life Sciences [q-bio], medicine.anatomical_structure, Otorhinolaryngology, Head and Neck Neoplasms, 030220 oncology & carcinogenesis, Neoplasms, Unknown Primary, Female, Surgery, medicine.symptom, Infection, business
Abstract

International audience; Introduction: Beside HPV infection, there is currently no evidence of association between head and neck squamous cell carcinomas and microbial infections. We report the case of a cervical squamous cell carcinoma by Mycoplasma hominis.Case summary: A 20-year-old woman, consulted for a swelling on the left cervical side. Clinical examination found a large fixed mass. Biological tests found no evidence of infection. Biopsies of the cervical lesion diagnosed an HPV negative squamous cell carcinoma. Microbiological tests of 16sRNA identification showed the presence of Mycoplasma hominis in the 3 specimens. The patient was treated by induction chemotherapy associated to antibiotherapy, followed by chemo-radiotherapy.Discussion: The present case suggests that oropharyngeal infection by Mycoplasma hominis might be more frequent than expected, that 16sRNA is an efficient technique to isolate this pathogen and finally that further studies are required to document its potential oncogenic role in head and neck squamous cell carcinomas.

Published
2020

12. Benefits of 3D printing applications in jaw reconstruction: A systematic review and meta-analysis

Author

Patrice Prognon, Nicolas Martelli, Judith Pineau, Hélène van den Brink, Carole Serrano, Groupe de Recherche et d'Accueil en Droit et Economie de la Santé (GRADES), Université Paris-Saclay, Immunité et cancer (U932), Université Paris Descartes - Paris 5 (UPD5)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), and CCSD, Accord Elsevier

Subjects
Models, Anatomic, [SHS.DROIT] Humanities and Social Sciences/Law, Additive manufacturing, 3D printing, Dentistry, Esthetics, Dental, [SHS]Humanities and Social Sciences, 03 medical and health sciences, [SHS.DROIT]Humanities and Social Sciences/Law, 0302 clinical medicine, Operating time, Medicine, ComputingMilieux_MISCELLANEOUS, Three-dimensional printing, Clinical outcome, business.industry, 030206 dentistry, Evidence-based medicine, [SDV.SP]Life Sciences [q-bio]/Pharmaceutical sciences, Random effects model, Surgery, Oral, [SDV.SP] Life Sciences [q-bio]/Pharmaceutical sciences, Meta-analysis, Jaw, Otorhinolaryngology, 030220 oncology & carcinogenesis, Three dimensional printing, Printing, Three-Dimensional, Systematic review, Surgery, [SHS] Humanities and Social Sciences, Oral Surgery, business
Abstract

International audience; Background: Three-dimensional (3D) printing has changed surgical practice over the past few years, especially in maxillofacial surgery. However, little is known about its real clinical impact. The objectives of our study were to identify clinical outcomes that have been evaluated in the literature regarding 3D printing applications in jaw reconstruction, and to quantify the impact of this technology on operating times.Methods: A systematic review was conducted by searching PubMed and EMBASE to collect comparative studies on 3D printing applications in jaw reconstruction. A meta-analysis of operating times was then performed. A Cochran's Q test was used to determine heterogeneity, and the overall effect size was calculated using a random effects model.Results: Fourteen studies were included in our review. Eighteen clinical end-points were identified, of which the most frequently reported were operating time (n = 5; 35.7%) and the final aesthetic result (n = 4; 28.6%). Operating times were significantly lower in the 3D printing groups, with an overall estimated effect of 21.2% (95% CI 10-33%; p < 0.001).Conclusion: The use of 3D printing in jaw reconstruction was associated with a significant reduction in operating times. The end-points evaluated differed largely among the studies. More studies with higher levels of evidence are needed to confirm our results.

Published
2019

13. Integrating Physical and Molecular Insights on Immune Cell Migration

Author

Raphaël Voituriez, Matthieu Piel, Ana-Maria Lennon-Duménil, Hélène D. Moreau, Immunité et cancer (U932), Université Paris Descartes - Paris 5 (UPD5)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Biologie Cellulaire et Cancer, Institut Curie [Paris]-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Laboratoire Jean Perrin (LJP), Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), ANR-11-LABX-0043,DCBIOL,Biologie des cellules dendritiques(2011), ANR-10-IDEX-0001,PSL,Paris Sciences et Lettres(2010), MOREAU, Hélène, Biologie des cellules dendritiques - - DCBIOL2011 - ANR-11-LABX-0043 - LABX - VALID, Initiative d'excellence - Paris Sciences et Lettres - - PSL2010 - ANR-10-IDEX-0001 - IDEX - VALID, Institut Curie [Paris], Institut Pierre-Gilles de Gennes pour la Microfluidique, Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Curie-Université Paris Descartes - Paris 5 (UPD5), and Institut Curie

Subjects
0301 basic medicine, [SDV.IMM] Life Sciences [q-bio]/Immunology, Immunology, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Biology, 03 medical and health sciences, Immune system, Antigen, Cell Movement, biophysics, Leukocytes, Animals, Humans, Immunology and Allergy, Cell migration, Cytoskeleton, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, cytoskeleton, Actomyosin, biochemical phenomena, metabolism, and nutrition, Actin cytoskeleton, microenvironment, Actin Cytoskeleton, 030104 developmental biology, Cellular Microenvironment, [SDV.IMM]Life Sciences [q-bio]/Immunology, bacteria, Site of action, Neuroscience, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Immune cell migration, Function (biology)
Abstract

International audience; The function of most immune cells depends on their ability to migrate through complex microenvironments, either randomly to patrol for the presence of antigens or directionally to reach their next site of action. The actin cytoskeleton and its partners are key conductors of immune cell migration as they control the intrinsic migratory properties of leukocytes as well as their capacity to respond to cues present in their environment. In this review we focus on the latest discoveries regarding the role of the actomyosin cytoskeleton in optimizing immune cell migration in complex environments, with a special focus on recent insights provided by physical modeling.

Published
2018

14. A Quantitative Multivariate Model of Human Dendritic Cell-T Helper Cell Communication

Author

Wassim Abou-Jaoudé, Céline Lévy-Leduc, Coline Trichot, Léa Karpf, Maximilien Grandclaudon, Marie Perrot-Dockès, Philémon Sirven, Frédérique Berger, Philippe Hupé, Omar Abouzid, Vassili Soumelis, Denis Thieffry, Julien Chiquet, Laure Sansonnet, Camille Chauvin, Immunité et cancer (U932), Institut Curie-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Curie, Mathématiques et Informatique Appliquées (MIA-Paris), AgroParisTech-Institut National de la Recherche Agronomique (INRA), Institut de biologie de l'ENS Paris (UMR 8197/1024) (IBENS), Département de Biologie - ENS Paris, École normale supérieure - Paris (ENS Paris)-École normale supérieure - Paris (ENS Paris)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM), PSL Research University (PSL), MINES ParisTech - École nationale supérieure des mines de Paris, Université Paris Descartes - Paris 5 (UPD5)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Curie [Paris], Institut de biologie de l'ENS Paris (IBENS), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Département de Biologie - ENS Paris, École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Paris sciences et lettres (PSL), Agence Nationale de la RechercheFrench National Research Agency (ANR) [ANR-16-CE15-0024-01, ANR-10-IDEX-0001-02 PSL*, ANR-11-LABX-0043, ANR-17-CE14-0025-02], Center of Clinical Inverstigation IGR-Curie [CIC IGR-Curie 1428], Ligue contre le CancerLigue nationale contre le cancer [EL2016.LNCC/VaS], ANRSANRSFrench National Research Agency (ANR), ARCAustralian Research Council, CCSD, Accord Elsevier, Institut National de la Recherche Agronomique (INRA)-AgroParisTech, École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), and Mines Paris - PSL (École nationale supérieure des mines de Paris)

Subjects
Adult, Cell signaling, Adolescent, [SDV]Life Sciences [q-bio], selection, Context (language use), Cell Communication, Computational biology, growth-factor-beta, Biology, stimulation, Models, Biological, General Biochemistry, Genetics and Molecular Biology, regulatory network, Young Adult, 03 medical and health sciences, 0302 clinical medicine, medicine, Humans, T-helper cell differentiation, Cells, Cultured, Aged, 030304 developmental biology, Systems immunology, 0303 health sciences, health, Dendritic Cells, T helper cell, Dendritic cell, Middle Aged, Interleukin-12, Coculture Techniques, Healthy Volunteers, [SDV] Life Sciences [q-bio], medicine.anatomical_structure, plasticity, Th17 Cells, DECIPHER, differentitation, 030217 neurology & neurosurgery, Function (biology), lineage, Interleukin-1
Abstract

International audience; Cell-cell communication involves a large number of molecular signals that function as words of a complex language whose grammar remains mostly unknown. Here, we describe an integrative approach involving (1) protein-level measurement of multiple communication signals coupled to output responses in receiving cells and (2) mathematical modeling to uncover input-output relationships and interactions between signals. Using human dendritic cell (DC)-T helper (Th) cell communication as a model, we measured 36 DC-derived signals and 17 Th cytokines broadly covering Th diversity in 428 observations. We developed a data-driven, computationally validated model capturing 56 already described and 290 potentially novel mechanisms of Th cell specification. By predicting context-dependent behaviors, we demonstrate a new function for IL-12p70 as an inducer of Th17 in an IL-1 signaling context. This work provides a unique resource to decipher the complex combinatorial rules governing DC-Th cell communication and guide their manipulation for vaccine design and immunotherapies.

Published
2019

15. HIV trafficking in host cells: motors wanted!

Author

Raphael Gaudin, Bruna Cunha de Alencar, Philippe Benaroch, Nathalie J. Arhel, Immunité et cancer (U932), Université Paris Descartes - Paris 5 (UPD5)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Génétique et Ecologie des Virus, Génétique des Virus et Pathogénèse des Maladies Virales, Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Descartes - Paris 5 (UPD5)-Institut Curie-Institut National de la Santé et de la Recherche Médicale (INSERM), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Diderot - Paris 7 (UPD7)

Subjects
Cells, [SDV]Life Sciences [q-bio], viruses, Dynein, myosin, Microtubules, kinesin, Virus, 03 medical and health sciences, Retrovirus, Molecular motor, Animals, Humans, Cytoskeleton, Actin, 030304 developmental biology, 0303 health sciences, dynein, biology, Molecular Motor Proteins, Cell Membrane, 030302 biochemistry & molecular biology, HIV, Biological Transport, cytoskeleton, Cell Biology, biology.organism_classification, Virology, Cell biology, retrovirus, [SDV.MP]Life Sciences [q-bio]/Microbiology and Parasitology, Viral replication, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, Kinesin, actin, microtubule
Abstract

International audience; Throughout the viral replication cycle, viral proteins, complexes, and particles need to be transported within host cells. These transport events are dependent on the host cell cytoskeleton and molecular motors. However, the mechanisms by which virus is trafficked along cytoskeleton filaments and how molecular motors are recruited and regulated to guarantee successful integration of the viral genome and production of new viruses has only recently begun to be understood. Recent studies on HIV have identified specific molecular motors involved in the trafficking of these viral particles. Here we review recent literature on the transport of HIV components in the cell, provide evidence for the identity and role of molecular motors in this process, and highlight how these trafficking events may be related to those occurring with other viruses.

Published
2013

16. Dissecting Effects of Anti-cancer Drugs and Cancer-Associated Fibroblasts by On-Chip Reconstitution of Immunocompetent Tumor Microenvironments

Author

Eugenio Martinelli, Luca Businaro, Vassili Soumelis, Ayako Yamada, Fanny Mermet-Meillon, Maria Carla Parrini, Weijing Han, Jacques Camonis, Floriane Pelon, Yasmine Khira, Giulia Fornabaio, Francesca Romana Bertani, Annamaria Gerardino, Gérard Zalcman, Stéphanie Descroix, Mélissande Cossutta, Marie Nguyen, Fatima Mechta-Grigoriou, Sophia S. Evans, Adele De Ninno, Davide Di Giuseppe, Philémon Sirven, Arianna Mencattini, Università degli Studi di Roma Tor Vergata [Roma], Croissance cellulaire, réparation et régénération tissulaires (CRRET), Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Centre National de la Recherche Scientifique (CNRS), Immunité et cancer (U932), Université Paris Descartes - Paris 5 (UPD5)-Institut Curie-Institut National de la Santé et de la Recherche Médicale (INSERM), Institute of Photonics and Nanotechnology, Consiglio Nazionale delle Ricerche [Roma] (CNR), Physico-Chimie-Curie (PCC), Centre National de la Recherche Scientifique (CNRS)-Institut Curie-Université Pierre et Marie Curie - Paris 6 (UPMC), Laboratoire d'Immunologie Clinique, Institut Curie, Institut Curie-Institut Curie, Service de pneumologie [CHU Caen], Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN), Département de Recherche Translationnelle (Plateforme BioPhenics), AP-HP Groupe Hospitalier Saint-Louis (Paris)-Institut Curie (Paris), Institut Curie-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Descartes - Paris 5 (UPD5)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre National de la Recherche Scientifique (CNRS)-Institut Curie [Paris]-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Chimie du CNRS (INC), Institut Curie [Paris], Hopital Saint-Louis [AP-HP] (AP-HP), and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut Curie [Paris]

Subjects
0301 basic medicine, Receptor, ErbB-2, [SDV]Life Sciences [q-bio], medicine.medical_treatment, Settore ING-INF/01, Cell Communication, ErbB-2, Cancer-Associated Fibroblasts, Trastuzumab, Tumor Microenvironment, skin and connective tissue diseases, lcsh:QH301-705.5, Antibody-dependent cell-mediated cytotoxicity, Tumor, 3. Good health, tumor-on-chip, HER2(+) breast cancer, cancer-associated fibroblasts, immunotherapy, live cell imaging, microfluidics, organ-on-chip, pre-clinical models, trastuzumab, tumor microenvironment, Animals, Antineoplastic Agents, Cattle, Cell Line, Tumor, Human Umbilical Vein Endothelial Cells, Humans, Immunocompetence, Neoplasm Invasiveness, Stromal Cells, Receptor, medicine.drug, Stromal cell, cancer on chip, General Biochemistry, Genetics and Molecular Biology, Cell Line, 03 medical and health sciences, Immune system, medicine, neoplasms, Tumor microenvironment, business.industry, Cancer, Immunotherapy, medicine.disease, 030104 developmental biology, lcsh:Biology (General), Cancer research, organs on chip, business
Abstract

Summary: A major challenge in cancer research is the complexity of the tumor microenvironment, which includes the host immunological setting. Inspired by the emerging technology of organ-on-chip, we achieved 3D co-cultures in microfluidic devices (integrating four cell populations: cancer, immune, endothelial, and fibroblasts) to reconstitute ex vivo a human tumor ecosystem (HER2+ breast cancer). We visualized and quantified the complex dynamics of this tumor-on-chip, in the absence or in the presence of the drug trastuzumab (Herceptin), a targeted antibody therapy directed against the HER2 receptor. We uncovered the capacity of the drug trastuzumab to specifically promote long cancer-immune interactions (>50 min), recapitulating an anti-tumoral ADCC (antibody-dependent cell-mediated cytotoxicity) immune response. Cancer-associated fibroblasts (CAFs) antagonized the effects of trastuzumab. These observations constitute a proof of concept that tumors-on-chip are powerful platforms to study ex vivo immunocompetent tumor microenvironments, to characterize ecosystem-level drug responses, and to dissect the roles of stromal components. : Inspired by the emerging technology of tumor-on-chip, Nguyen et al. reconstituted ex vivo a human tumor microenvironment (HER2+ breast cancer), characterized the ecosystem-level responses to the drug trastuzumab (Herceptin), and dissected the roles of stromal components (immune cells and fibroblasts), demonstrating the power of immunocompetent tumors-on-chip for preclinical drug studies. Keywords: tumor microenvironment, organ-on-chip, tumor-on-chip, trastuzumab, HER2+ breast cancer, cancer-associated fibroblasts, live cell imaging, microfluidics, pre-clinical models, immunotherapy

Published
2018

17. TSAP6 Facilitates the Secretion of Translationally Controlled Tumor Protein/Histamine-releasing Factor via a Nonclassical Pathway

Author

Nathalie Amzallag, Robert Amson, Bruno Goud, Adam Telerman, Clotilde Théry, Brent Passer, Elodie Segura, David Allanic, Immunité et cancer (U932), Université Paris Descartes - Paris 5 (UPD5)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris sciences et lettres (PSL), Compartimentation et dynamique cellulaires (CDC), Centre National de la Recherche Scientifique (CNRS)-Institut Curie [Paris]-Université Pierre et Marie Curie - Paris 6 (UPMC), Laboratoire de Biologie et de Pharmacologie Appliquée (LBPA), École normale supérieure - Cachan (ENS Cachan)-Centre National de la Recherche Scientifique (CNRS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut Curie [Paris]-Centre National de la Recherche Scientifique (CNRS), Université Paris Descartes - Paris 5 (UPD5)-Institut Curie-Institut National de la Santé et de la Recherche Médicale (INSERM), PSL Research University (PSL), and Centre National de la Recherche Scientifique (CNRS)-Institut Curie-Université Pierre et Marie Curie - Paris 6 (UPMC)

Subjects
[SDV]Life Sciences [q-bio], [SDV.CAN]Life Sciences [q-bio]/Cancer, Cell Cycle Proteins, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Biology, Biochemistry, Exosome, Cell Line, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Translationally-controlled tumor protein, Biomarkers, Tumor, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Secretion, Cycloheximide, Molecular Biology, 030304 developmental biology, Oncogene Proteins, 0303 health sciences, Secretory Vesicles, Endoplasmic reticulum, Nuclear Proteins, Tumor Protein, Translationally-Controlled 1, Cell Biology, Brefeldin A, Transmembrane protein, Neoplasm Proteins, Cell biology, Protein Transport, chemistry, Membrane protein, 030220 oncology & carcinogenesis, biology.protein, Translationally controlled tumour protein, Oxidoreductases
Abstract

International audience; Translationally controlled tumor protein (TCTP) is cytoplasmic and structurally related to guanine-nucleotide free chaperones. TCTP (also called histamine-releasing factor) has been described previously as a secreted protein that participates in inflammatory responses by promoting the release of histamine. How TCTP is eventually exported out of the cell to promote such activities is unknown. Here we show that TCTP secretion was insensitive to either brefeldin A or monensin, suggesting that it proceeds via an endoplasmic reticulum/Golgi-independent or nonclassical pathway. Moreover, our analyses also suggest that secreted TCTP originates from pre-existing pools. TSAP6, a p53-inducible 5-6 transmembrane protein, was found to interact with TCTP in a yeast two-hybrid hunt. GST pull down assays confirmed their direct interaction, and immunofluorescence analysis revealed their partial co-distribution to vesicular-like structures at the plasma membrane and around the nucleus. Functionally, the overexpression of TSAP6 consistently leads to enhanced secretion of both endogenously and exogenously expressed TCTP. Finally, we found TCTP in preparations of small secreted vesicles called exosomes, which have been suggested as a possible pathway for nonclassical secretion. Overexpression of TSAP6 also increased TCTP levels in exosome preparations. Altogether, these data identify a novel role for TSAP6 in the export of TCTP and indicate that this multipass membrane protein could have a general role in the regulation of vesicular trafficking and secretion.

Published
2004

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